Assessment of disease activity and damage in SLE: Are we there yet?

Systemic Lupus Erythematosus is a systemic autoimmune disease characterized by a great heterogenicity in course and clinical manifestations. Although prognosis improved in the last decades of the 20th century, mortality remains higher than in the general population and uncontrolled disease activity and therapy-related adverse effects have been identified as major contributors to damage accrual and poor outcomes. Assessment of disease activity and damage in SLE represents a great challenge even to the expert rheumatologist. Global disease activity indices are tools developed to assess activity across multiple organ systems. Several disease activity indices have been developed over the years, each with its own strengths and weaknesses, and knowing them is essential for understanding research studies, such as clinical trials, in which they are used. Organ-specific activity indices have been developed concurrently to represent organ involvement such as glomerulonephritis, cutaneous and musculoskeletal lupus manifestations. Regarding damage, the SLICC/ACR damage index has proven to be an effective tool for damage accrual assessment, yet not devoid of drawbacks. This review provides an overview of the most frequently utilized indices developed for the assessment of activity and damage in SLE highlighting their pros and cons when applied to the research and clinical setting.

New onset sarcoidosis following biologic treatment in patients with seronegative inflammatory arthritis: A case series and systematic literature review.

OBJECTIVE: To report cases of new onset sarcoidosis upon biologic (bDMARDs) treatment administration in patients with seronegative inflammatory arthritis in a real-life cohort, alongside a systematic literature review (SLR) on this topic. METHODS: We performed a retrospective analysis on clinical records of patients with seronegative arthritis followed up in a monocentric cohort who underwent bDMARDs treatment due to the underlying rheumatic disease and described any newly diagnosed sarcoidosis in this cohort. Only ascertained cases with available radiological and/or histological documentation were considered. A SLR on new-onset sarcoidosis in seronegative arthritis receiving bDMARDs was performed across MEDLINE (through PubMed), Scopus and Ovid (Cochrane, Embase) electronic databases using appropriate strings. RESULTS: In our cohort, 4 new-onset cases of sarcoidosis were reported among patients with seronegative inflammatory arthritis receiving biologics. Three out of 4 patients were receiving anti-tumor necrosis factor alpha (TNFα) while 1 patient was on secukinumab (anti-IL17A) prior to sarcoidosis onset. The SLR disclosed 46 new-onset sarcoidosis cases upon biological treatment for seronegative arthritis, of whom 43 occurred during treatment with anti-TNFα, while 3 during anti-IL-17A therapy. In our cohort as well as in the majority of cases reported in the SLR, sarcoidosis presented with lymph nodal and lung involvement and displayed a benign course with spontaneous resolution in about 1 fourth of the cases. CONCLUSION: The use of biologics may relate to the onset of sarcoidosis; hence, clinicians must remain aware of the potential occurrence or reactivation of sarcoidosis when starting biologic treatment in patients with inflammatory arthritis, performing adequate patient assessment and surveillance. Since TNFα inhibitors may represent a therapeutic option for sarcoidosis, further evaluation on larger cohorts is needed to investigate any causal link with the development of sarcoidosis.

Characterization of Serum Cytokine Profiles of Patients with Active Lupus Nephritis.

Cytokines contribute to the pathogenesis of lupus nephritis (LN), yet their value as prognostic biomarkers is still debated. We aimed to describe the serum cytokines' profiles and prospectively assess correlations with disease features and renal response in a multicentric cohort of consecutive adult patients with biopsy-proven active LN. Cytokine associations with clinical and serological data were performed at LN diagnosis (T0), and at 3 (T3) and 6 months (T6) of follow up. Renal response according to EULAR definition was assessed at T3, T6 and T12. BAFF and interleukin (IL)-37 were measured by ELISA; IL-2, IL-10, IL-17A and IL-18 by a bead-based multiplex cytokine assay (Luminex). Thirty-nine patients with active LN (age 40.5 ± 15.6 years; F 71.8%; 84.6% proliferative LN) were enrolled, of whom twenty-nine displayed complete longitudinal records. At T0, we observed higher levels of IL-37 and IL-17 in proliferative vs. non-proliferative LN (IL-37: 0.0510 (0.0110-0.2300) vs. 0.0000 (0.0000-0.0397) ng/mL, p = 0.0441; IL-17: 2.0920 (0.5125-17.9400) vs. 0.0000 (0.0000-0.6025) pg/mL, p = 0.0026, respectively), and positive correlations between IL-10 and 24 h proteinuria (r = 0.416, p = 0.0249) and anti-dsDNA levels (r = 0.639, p = 0.0003). BAFF was higher in patients with low complement (p < 0.0001). We observed a sustained correlation between BAFF and IL-10 throughout T6 (r = 0.654, p = 0.0210). Higher baseline IL-37 and BAFF levels were associated with renal response at T3 and T6, respectively, while baseline IL-18 levels were higher in patients achieving response at T12. Our study highlights the complexity of the cytokine network and its potential value as a marker of active LN and renal response.

Detection of Myositis Autoantibodies by Multi-Analytic Immunoassays in a Large Multicenter Cohort of Patients with Definite Idiopathic Inflammatory Myopathies.

BACKGROUND: The usefulness of myositis-specific autoantibodies (MSAs) and myositis-associated autoantibodies (MAAs) for the assessment of idiopathic inflammatory myopathies (IIMs) is acknowledged, but laboratory standardization remains a challenge. We detected MSAs/MAAs by multi-analytic line immunoassay (LIA) and particle-based multi-analyte technology (PMAT) in a multicenter cohort of patients with IIMs. METHODS: We tested the sera from 411 patients affected with definite IIM, including 142 polymyositis (PM), 147 dermatomyositis (DM), 19 cancer-associated myositis, and 103 overlap myositis syndrome (OM), and from 269 controls. MSAs/MAAs were determined by 16Ags LIA in all sera, and anti-HMGCR by ELISA in 157/411 IIM sera and 91/269 control sera. The analytical specificity of LIA/HMGCR ELISA was compared with that of PMAT in 89 MSA+ IIM sera. RESULTS: MSAs/MAAs were positive in 307/411 (75%) IIM patients and 65/269 (24%) controls by LIA (Odds Ratio 9.26, 95% CI 6.43-13.13, p < 0.0001). The sensitivity/specificity of individual MSAs/MAAs were: 20%/100% (Jo-1), 3%/99.3% (PL-7), 4%/98.8% (PL-12), 1%/100% (EJ), 0.7%/100% (OJ), 9%/98% (SRP), 5.6%/99.6% (TIF1γ), 4.6%/99.6% (MDA5), 8%/96% (Mi-2), 1.5%/98% (NXP2), 1.7%/100% (SAE1), 4%/92% (Ku), 8.5%/99% (PM/Scl-100), 8%/96% (PM/Scl-75), and 25.5%/79% (Ro52). Anti-HMGCR was found in 8/157 (5%) IIM patients and 0/176 (0%) controls by ELISA (p = 0.007). Concordance between LIA/HMGCR ELISA and PMAT was found in 78/89 (88%) samples. Individual MSAs detected by LIA were associated with IIM subsets: Jo-1 with PM and OM, PL-12 with OM, Mi-2, TIF1γ, and MDA5 with DM, SRP with PM, and PM/Scl-75/100 with OM (p < 0.001 for all). CONCLUSIONS: Since MSAs are mostly mutually exclusive, multi-specific antibody profiling seems effective for a targeted clinical-serologic approach to the diagnosis of IIMs.

Translational implications of newly characterized pathogenic pathways in systemic lupus erythematosus.

Improved characterization of relevant pathogenic pathways in systemic lupus erythematosus (SLE) has been further delineated over the last decades. This led to the development of targeted treatments including belimumab and anifrolumab, which recently became available in clinics. Therapeutic targets in SLE encompass interferon (IFN) signaling, B-T costimulation including immune checkpoints, and increasing modalities of B lineage targeting, such as chimeric antigen receptor (CAR) T cells directed against CD19 or sequential anti-B cell targeting. Patient profiling based on characterization of underlying molecular abnormalities, often performed through comprehensive omics analyses, has recently been shown to better predict patients' treatment responses and also holds promise to unravel key molecular mechanisms driving SLE. SLE carries two key signatures, namely the IFN and B lineage/plasma cell signatures. Recent advances in SLE treatments clearly indicate that targeting innate and adaptive immunity is successful in such a complex autoimmune disease. Although those signatures may interact at the molecular level and provide the basis for the first selective treatments in SLE, it remains to be clarified whether these distinct treatments show different treatment responses among certain patient subsets. In fact, notwithstanding the remarkable amount of novel clues for innovative SLE treatment, harmonization of big data within tailored treatment strategies will be instrumental to better understand and treat this challenging autoimmune disorder. This review will provide an overview of recent improvements in SLE pathogenesis, related insights by analyses of big data and machine learning as well as technical improvements in conducting clinical trials with the ultimate goal that translational research results in improved patient outcomes.

Is per-protocol kidney biopsy required in lupus nephritis?

Baseline kidney biopsy is recommended in lupus nephritis (LN). Biopsy allows to classify different forms of LN and differentiate other forms of renal involvement, such as tubulo-interstitial nephritis or thrombotic microangiopathy. The indications for repeat biopsy are more controversial. Some authors feel that good clinical monitoring is sufficient to assess prognosis and make therapeutic decisions. Based on the recently demonstrated discordance between clinical and histological response, some physicians recommend per-protocol biopsies either at 6 months in stable patients to verify the response to induction therapy, or after one-to-two years to assess treatment efficacy and tune the duration of maintenance therapy. Others recommend repeating kidney biopsy in case of incomplete response or to discriminate between active and chronic lesions. By definition, a per-protocol kidney biopsy differs from a repeat biopsy in that the former is foreseen at fixed timepoints, regardless of the clinical response. Although any decision should always consider the patient's overall clinical condition, there are no doubts that repeat kidney biopsy represents a useful tool in difficult cases to evaluate treatment response, modulate treatment intensity, and predict long-term renal outcome both in quiescent lupus and during flares. How to harmonize per-protocol biopsies in the LN course remains challenging.

Should ACR/EULAR criteria be revised changing the RF and ACPA scores?

Current classification criteria for rheumatoid arthritis (RA) encompass clinical and immunological items and are capable of correctly identifying the majority of symptomatic RA patients. The presence of positive rheumatoid factor (RF) and/or and anti-cyclic citrullinated protein/peptide antibodies (ACPA) gaining increasing importance according to their serological titer eases the recognition of RA, yet the debate is open on whether this scoring system ought to be optimized by hierarchizing ACPA or the combination of ACPA and RF over single positivity, prioritizing specificity over sensitivity. The risk of misdiagnosis and misclassification are often entangled, yet they are not the same. In fact, while ideal diagnosis requires 100% sensitivity and specificity, classification criteria are conceived to gather a homogeneous patient population, favoring specificity over sensitivity. Nevertheless, as they are frequently summoned to support the diagnostic process in clinical practice, issues arise on how comprehensive those should be and on how frequently they should be updated in light of novel acquisitions regarding measurable RA-related abnormalities. In this viewpoint two different views on the topic are confronted, discussing the performance of available criteria and the potentiality and pitfalls of their refinement according to novel data on ACPA and RF contribution and emergence of newly discovered specificities.

MicroRNAs in idiopathic inflammatory myopathies: state-of-the-art and future perspectives.

PURPOSE OF REVIEW: Idiopathic inflammatory myopathies (IIMs) are a group of rare autoimmune disorders characterized by muscle weakness and inflammation. MicroRNAs (miRNAs) are the main class of small noncoding RNAs regulating a wide range of physiological and pathological processes and play a role in mediating autoimmunity and inflammation. In this review, we summarize the latest knowledge on the role of miRNAs in systemic autoimmune diseases with particular focus on IIMs. RECENT FINDINGS: Study on miRNA expression in IIMs is helping in understanding the pathogenetic basis of the disease at a tissue and systemic level. Several miRNAs, even with a muscle-specific expression (myomiRs), have been shown to be involved in immune and nonimmune mechanisms of myofiber damage. MiRNAs modulate and orchestrate the local inflammatory infiltrate and could be used as potential biomarkers as they correlate with disease activity and response to therapy. SUMMARY: IIMs comprise different clinical phenotypes and still little is known about the molecular signature of each subset. Further research about miRNA profiling will provide additional insights in the disease characterization with an expected impact on the therapeutic strategies.

Interstitial lung disease with and without progressive fibrosing phenotype in patients with idiopathic inflammatory myopathies: data from a large multicentric cohort.

OBJECTIVES: Patients with connective tissue diseases can develop interstitial lung disease (ILD), leading to a progressive fibrosing ILD (PF-ILD) phenotype in some cases. We aimed to investigate the occurrence of PF-ILD in idiopathic inflammatory myopathies (IIMs), and factors potentially predicting this phenotype. Secondary aims were to assess the radiological pattern and factors associated with IIMs-ILD. METHODS: Patients with IIMs from our multicentric prospective cohort were retrospectively evaluated. Data were recorded at IIMs and ILD diagnosis, and during follow-up. Patients with ILD were classified according to the predominant high-resolution CT (HRCT) pattern: non-specific interstitial pneumonia (NSIP), usual interstitial pneumonia (UIP) and organising pneumonia (OP). PF-ILD was defined according to the 2022 American Thoracic Society (ATS), European Respiratory Society (ERS), Japanese Respiratory Society (JRS) and Latin American Thoracic Society (ALAT) guidelines. Univariate and multivariate analyses were performed to identify factors associated to ILD and to PF-ILD. RESULTS: Of 253 patients with IIMs, 125 (49%) had ILD: 99 (78%) at IIMs diagnosis and 26 (22%) during follow-up (21/26 within 5 years). Multivariate analysis identified anti-Jo-1, anti-MDA5, anti-Ro52, high score on manual muscle test, mechanic's hands and Raynaud's phenomenon as independently associated with ILD. The predominant HRCT pattern was NSIP (50% of patients), followed by UIP (28%) and OP (22%). At 1-year follow-up, PF-ILD occurred in 18% of IIMs-ILD. PF-ILD was predicted by anti-MDA5, heliotropic rash, xerostomia and xerophthalmia at univariate but not at multivariate analysis. CONCLUSION: Patients with IIM should be carefully screened for ILD at IIMs diagnosis and yearly during follow-up. All patients with IIMs-ILD should be carefully monitored to capture ILD progression since a consistent proportion of them are expected to develop PF-ILD.

The SLE-DAS provides an accurate and feasible flare tool in the clinical setting: a validation study.

OBJECTIVE: To assess the criterion validity of the SLE disease activity score (SLE-DAS) flare tool and compare its performance in identifying flares against other instruments. METHODS: Patients with SLE fulfilling SLE-DAS low disease activity at baseline were included from two academic lupus clinics. During follow-up, flares were identified by the senior attending clinician, applying the expert-consensus-based definition as gold-standard. The first clinical flare from flaring patients, and the first visit after baseline in patients without flares were analysed. In each no flare/flare visits, we assessed flares by SLE-DAS (score increase ≥1.72), classic-SELENA Flare Index (c-SFI), revised-SFI (r-SFI), and SLEDAI-2K (score increase ≥4). We estimated the sensitivity, specificity, and Cohen's Kappa agreement of each flare tool against the gold-standard. RESULTS: A total of 442 patients were included and followed-up for 22.9 ± 14.2 months. Incidence of flares was 8.19/100 patient-years, with 69 patients experiencing flares. The SLE-DAS identified 96.6% of the expert-defined flares implying a treatment change and classified 28.0% of those as moderate/severe. Sensitivity and specificity for the gold-standard flare definition were: SLE-DAS 97.1% and 97.3%, c-SFI 88.4% and 98.1%, r-SFI 88.4% and 96.8%, SLEDAI-2K 56.5% and 99.2%, respectively. Kappa coefficients of these instruments were 0.902 (95%CI: 0.847-0.957), 0.870 (95%CI: 0.805-0.935), 0.832 (95%CI: 0.761-0.903), and 0.663 (95%CI: 0.557-0.769), respectively. The number of flare misclassifications was lowest with the SLE-DAS, and highest with the SLEDAI-2K. CONCLUSION: The SLE-DAS accurately identifies and categorizes flares as mild or moderate/severe. It is feasible and, thus, may help the physicians' treatment decisions in the clinical practice setting.

CCL18 as a Biomarker of Interstitial Lung Disease (ILD) and Progressive Fibrosing ILD in Patients with Idiopathic Inflammatory Myopathies.

OBJECTIVES: To assess CCL18 and OX40L as biomarkers of interstitial lung disease (ILD) and/or progressive fibrosing (PF-) ILD in idiopathic inflammatory myopathies (IIMs). METHODS: Patients with IIMs seen in our center from July 2020 to March 2021 were consecutively enrolled. ILD was detected by high-resolution CT. CCL18 and OX40L serum levels were measured by validated ELISA assays in 93 patients and 35 controls. At the 2-year follow-up, PF-ILD was evaluated according to the INBUILD criteria. RESULTS: ILD was diagnosed in 50 (53.7%) patients. CCL18 serum levels were higher in IIMs patients vs. controls (232.9 [IQR 134.7-399.07] vs. 48.4 [29.9-147.5], p < 0.0001), with no difference for OX40L. IIMs-ILD patients exhibited higher levels of CCL18 than those without ILD (306.8 [190.8-520.5] vs. 162 [75.4-255.8], p < 0.0001). High CCL18 serum levels were independently associated with IIMs-ILD diagnosis. At follow-up, 22/50 (44%) patients developed a PF-ILD. Patients who developed PF-ILD had higher CCL18 serum levels than non-progressors (511 [307-958.7] vs. 207.1 [149.3-381.7], p < 0.0001). Multivariate logistic regression analysis revealed CCL18 as the only independent predictor of PF-ILD (OR 1.006 [1.002-1.011], p = 0.005). CONCLUSIONS: Although in a relatively small sample, our data suggest that CCL18 is a useful biomarker in IIMs-ILD, particularly in the early identification of patients at risk of developing PF-ILD.

Early and Late Response and Glucocorticoid-Sparing Effect of Belimumab in Patients with Systemic Lupus Erythematosus with Joint and Skin Manifestations: Results from the Belimumab in Real Life Setting Study-Joint and Skin (BeRLiSS-JS).

AIM: To assess the efficacy of belimumab in joint and skin manifestations in a nationwide cohort of patients with SLE. METHODS: All patients with skin and joint involvement enrolled in the BeRLiSS cohort were considered. Belimumab (intravenous, 10 mg/kg) effectiveness in joint and skin manifestations was assessed by DAS28 and CLASI, respectively. Attainment and predictors of DAS28 remission (<2.6) and LDA (≥2.6, ≤3.2), CLASI = 0, 1, and improvement in DAS28 and CLASI indices ≥20%, ≥50%, and ≥70% were evaluated at 6, 12, 24, and 36 months. RESULTS: DAS28 < 2.6 was achieved by 46%, 57%, and 71% of patients at 6, 12, and 24 months, respectively. CLASI = 0 was achieved by 36%, 48%, and 62% of patients at 6, 12, and 24 months, respectively. Belimumab showed a glucocorticoid-sparing effect, being glucocorticoid-free at 8.5%, 15.4%, 25.6%, and 31.6% of patients at 6, 12, 24, and 36 months, respectively. Patients achieving DAS-LDA and CLASI-50 at 6 months had a higher probability of remission at 12 months compared with those who did not (p = 0.034 and p = 0.028, respectively). CONCLUSIONS: Belimumab led to clinical improvement in a significant proportion of patients with joint or skin involvement in a real-life setting and was associated with a glucocorticoid-sparing effect. A significant proportion of patients with a partial response at 6 months achieved remission later on during follow-up.

Size-Exclusion Chromatography Combined with Ultrafiltration Efficiently Isolates Extracellular Vesicles from Human Blood Samples in Health and Disease.

There is still a need for an efficient method for the isolation of extracellular vesicles (EVs) from human blood that provides a reliable yield with acceptable purity. Blood is a source of circulating EVs, but soluble proteins and lipoproteins hamper their concentration, isolation, and detection. This study aims to investigate the efficiency of EV isolation and characterization methods not defined as "gold standard". EVs were isolated from human platelet-free plasma (PFP) of patients and healthy donors through size-exclusion chromatography (SEC) combined with ultrafiltration (UF). Then, EVs were characterized using transmission electron microscopy (TEM), imaging flow cytometry (IFC), and nanoparticle tracking analysis (NTA). TEM images showed intact and roundish nanoparticles in pure samples. IFC analysis detected a prevalence of CD63+ EVs compared to CD9+, CD81+, and CD11c+ EVs. NTA confirmed the presence of small EVs with a concentration of ~1010 EVs/mL that were comparable when stratifying the subjects by baseline demographics; conversely, concentration differed according to the health status across healthy donors and patients affected with autoimmune diseases (130 subjects in total, with 65 healthy donors and 65 idiopathic inflammatory myopathy (IIM) patients). Altogether, our data show that a combined EV isolation method, i.e., SEC followed by UF, is a reliable approach to isolate intact EVs with a significant yield from complex fluids, which might characterize disease conditions early.

New onset and flare of rheumatic diseases following COVID-19 vaccination are mild and respond well to treatment: 9-month follow-up data from a single centre cohort.

OBJECTIVES: Anti-COVID-19 vaccines have proved to be effective and well tolerated. Great attention is now being paid to the characterisation of possible adverse events associated to their administration. We report a case series of suspected rheumatic diseases (RDs) following anti-COVID-19 vaccination. METHODS: We included patients evaluated at first-aid rheumatologic consultancy and at rheumatologic outpatient and inpatient clinic at Padova University Hospital between May and September 2021 presenting with a RD within 30 days after an anti-COVID-19 vaccine dose. Our selection was in accordance with the World Health Organisation guidelines for adverse event following immunisation (AEFI) surveillance. Patients were regularly re-evaluated by telemedicine or face-to-face visit. RESULTS: We identified 30 cases of RD following vaccination: 24 (80.0%) new onsets and 6 (20.0%) flares. Most of patients (76.6%) received the BNT162b2 vaccine. The mean time to RD onset/flare was 12±9 days. The most common manifestations were inflammatory arthritis (40.0%), rheumatic polymyalgia (33.3%) and adult-onset Still's disease (13.3%). At the last FU visit (9.6±2.2 months), 83.3% of patients showed complete response to first- or second-line therapy, 13.3% a partial response and one patient (3.3%) was still experiencing an active disease. CONCLUSIONS: Considering the amount of vaccine doses administered during the evaluation period we overall detected a limited number of cases. We noted a clear prevalence of autoinflammatory conditions and seronegative manifestations. The great majority of patients had mild features and showed a good response to therapy.

Early Increase of Circulating Transitional B Cells and Autoantibodies to Joint-Related Proteins in Patients With Metastatic Melanoma Developing Checkpoint Inhibitor-Induced Inflammatory Arthritis.

OBJECTIVE: To investigate potential associations between B cell-related immunologic changes and development of inflammatory arthritis (IA) after treatment with immune checkpoint inhibitors (ICIs). METHODS: Patients who developed ICI-induced IA (ICI-IA) and patients who did not develop immune-related adverse events (non-IRAE) after receiving ICIs to treat metastatic melanoma were consecutively recruited. Blood samples were collected at the time of ICI-IA occurrence and at different time points during treatment. Peripheral blood B cell subsets during ICI treatment were analyzed by flow cytometry. Rheumatoid factor, anti-citrullinated protein antibodies, and antibodies against joint-related proteins were measured. RESULTS: Proportions of CD19+ B cells were higher in patients with ICI-IA (n = 7) compared to patients with non-IRAE (n = 15) (median 11.7% [interquartile range (IQR) 9.7-16.2%] versus 8.1% [IQR 5.7-11.0%]; P = 0.03). The proportion and absolute numbers of transitional CD19+CD10+CD24high CD38high B cells were increased in patients with ICI-IA compared to non-IRAE patients (median 8.1% [IQR 4.9-12.1%] versus 3.6% [IQR 1.9-4.9%]; median 10.7 cells/µl [IQR 8.9-19.6] versus 4.4 cells/µl [IQR 2.3-6.6]; P < 0.01 for both). In addition, higher levels of transitional B cells were associated with development of ICI-IA (odds ratio 2.25 [95% confidence interval 1.03-4.9], P = 0.04). Transitional B cells increased before the onset of overt ICI-IA and decreased between the active and quiescent stages of ICI-IA (P = 0.02). Autoantibodies to type II collagen epitopes were detected in up to 43% of ICI-IA patients compared to none of the non-IRAE patients (P = 0.02). CONCLUSION: Development of ICI-IA is accompanied by an increase in transitional B cells and by production of autoantibodies to joint-related proteins. Monitoring of B cell-driven abnormalities upon ICI treatment may help earlier recognition of ICI-IA.

B Cell Kinetics upon Therapy Commencement for Active Extrarenal Systemic Lupus Erythematosus in Relation to Development of Renal Flares: Results from Three Phase III Clinical Trials of Belimumab.

Renal flares constitute major determinants of poor prognosis in people living with systemic lupus erythematosus (SLE). The aim of the present study was to investigate changes in B cell subsets in relation to renal flares upon initiation of standard therapy (ST) plus belimumab or placebo in patients with SLE. Using data from the BLISS-76, BLISS-SC, and BLISS Northeast Asia trials, we investigated associations of relative to baseline rapid (through week 8) and early (through week 24) percentage changes in circulating CD19+ B cell subsets characterised through flow cytometry, anti-dsDNA antibodies, and complement levels with the occurrence of renal flares over one year. Patients who developed renal flares showed more prominent rapid decreases in CD19+CD20+CD138+ short-lived plasma cells (-50.4% vs. -16.7%; p = 0.019) and CD19+CD20-CD27bright plasmablasts (-50.0% vs. -29.9%; p = 0.020) compared to non-flaring patients, followed by a subsequent return. Less prominent rapid reductions in CD19+CD27-CD24brightCD38bright transitional B cells (-42.9% vs. -75.0%; p = 0.038) and CD19+CD20-CD138+ peripheral long-lived plasma cells (-11.3% vs. -29.2%; p = 0.019) were seen in belimumab-treated-but not placebo-treated-patients who developed renal flares compared to belimumab-treated patients who did not. Rapid and early changes in anti-dsDNA or complement levels showed no clear association with renal flares. In summary, a rapid drop followed by a subsequent return in circulating short-lived plasma cells and plasmablasts upon treatment for active extra-renal SLE portended renal flares, indicating a need for therapeutic adjustments in patients showing such B cell patterns. Rapid decreases in transitional B cells and peripheral long-lived plasma cells upon belimumab therapy commencement may signify a greater protection against renal flares. B cell kinetics may prove useful in early drug evaluation.

Anti-MDA5 dermatomyositis: an update from bench to bedside.

PURPOSE OF REVIEW: This review summarizes the recent developments about anti-MDA5 antibody positive dermatomyositis with a focus on its pathogenesis, clinical features and treatment options of rapidly progressive interstitial lung disease, its most ominous complication. RECENT FINDINGS: Anti-MDA5+ dermatomyositis has a heterogeneous clinical spectrum with different patient subsets exhibiting widely different outcomes; severe acute interstitial lung disease is the main factor impacting prognosis. The pathogenetic role of anti-MDA5 antibodies is an active area of investigation. SUMMARY: Anti-MDA5+ dermatomyositis has a wider spectrum of manifestations than previously thought. A high index of suspicion is needed not to miss atypical presentations. In the setting of acute interstitial lung involvement, once a confident diagnosis is made, an aggressive approach with early combined immunosuppression affords the best chances of survival.

B cells in systemic lupus erythematosus: Targets of new therapies and surveillance tools.

B cell hyperactivity is a hallmark of the complex autoimmune disease systemic lupus erythematosus (SLE), which has justified drug development focusing on B cell altering agents during the last decades, as well as the off-label use of B cell targeting biologics. About a decade ago, the anti-B cell activating factor (BAFF) belimumab was the first biological agent to be licensed for the treatment of adult patients with active yet non-renal and non-neuropsychiatric SLE, to later be expanded to include treatment of pediatric SLE and, recently, lupus nephritis. B cell depletion is recommended as an off-label option in refractory cases, with the anti-CD20 rituximab having been the most used B cell depleting agent to date while agents with a slightly different binding specificity to CD20 such as obinutuzumab have also shown promise, forming a part of the current pipeline. In addition, terminally differentiated B cells have also been the targets of experimental therapies, with the proteasome inhibitor bortezomib being one example. Apart from being promising drug targets, B and plasma cells have also shown promise in the surveillance of patients with SLE, especially for monitoring B cell depleting or B cell altering therapies. Inadequate B cell depletion may signify poor expected clinical response to rituximab, for example, while prominent reductions in certain B cell subsets may signify a protection against flare development in patients treated with belimumab. Toward an era with a richer therapeutic armamentarium in SLE, including to a large extent B cell altering treatments, the challenge that emerges is to determine diagnostic means for evidence-based therapeutic decision-making, that uses clinical information, serological markers, and gene expression patterns to guide individualized precision strategies.

Caveats and pitfalls in defining low disease activity in systemic lupus erythematosus.

The treat-to-target strategy has been recently suggested in the management of Systemic Lupus Erythematosus (SLE). Lupus Low Disease Activity State (LLDAS) and Definitions Of Remission In SLE (DORIS) remission were outlined as two concentric targets. The achievement of LLDAS was shown to be associated with lower frequency of SLE flare, decreased damage progression, better quality of life, and reduced mortality. In addition, LLDAS has successfully been tested in post-hoc analyses of a number of randomized controlled trials. However, it has been recently underlined that LLDAS includes a high proportion of patients in remission, raising the question if these endpoints are sufficiently distinct to consider their separation clinically relevant. Some studies suggest that the protective effect of LLDAS on damage might be due to the inclusion of patients who are in remission. Notably, clinical low disease activity (LDA) seems to be uncommon in SLE due to the relapsing-remitting pattern of the disease, in which low level of activity only occurs transiently. Moreover, since the domains included in LLDAS have several limitations, such as the use of a binomial disease activity index, the exclusion of some mild manifestations and the consideration of items subjected to variability (physician global assessment and glucocorticoids dose), not all patients in LDA are adequately represented by LLDAS.